Discovery of a 5H-Benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (MK-2461) Inhibitor of c-Met Kinase for the Treatment of Cancer

作者：Katz Jason D^*; Jewell James P; Guerin David J; Lim Jongwon; Dinsmore Christopher J; Deshmukh Sujal V; Pan Bo Sheng; Marshall C Gary; Lu Wei; Altman Michael D; Dahlberg William K; Davis Lenora; Falcone Danielle; Gabarda Ana E; Hang Gaozhen; Hatch Harold; Holmes Rachael; Kunii Kaiko; Lumb Kevin J; Lutterbach Bart; Mathvink Robert; Nazef Naim; Patel Sangita B; Qu Xianlu; Reilly John F; Rickert Keith W; Rosenstein Craig; Soisson Stephen M; Spencer Kerrie B

来源：Journal of Medicinal Chemistry, 2011, 54(12): 4092-4108.

DOI：10.1021/jm200112k

c-Met is a transmembrane tyrosine kinase that mediates activation of several signaling pathways implicated in aggressive cancer phenotypes. In recent years, research into this area has highlighted c-Met as an attractive cancer drug target, triggering a number of approaches to disrupt aberrant c-Met signaling. Screening efforts identified a unique class of 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one kinase inhibitors, exemplified by 1. Subsequent SAR studies led to the development of 81 (MK-2461), a potent inhibitor of c-Met that was efficacious in preclinical animal models of tumor suppression. In addition, biochemical studies and X-ray analysis have revealed that this unique class of kinase inhibitors binds preferentially to the activated (phosphorylated) form of the kinase. This report details the development of 81 and provides a description of its unique biochemical properties.

• 出版日期2011-6-23